Neurokinin-1 receptor antagonists

ABSTRACT

Compounds having the general formula  
     R 1 R 2 N—CH 2 CH 2 —CHAr 1 —CH 2 —NR 3 —CO—R 4   (I)  
     wherein R 1 , R 2 , R 3 , R 4  and Ar are as defined in the specification, methods of making such compounds, methods of using such compounds for the treatment of diseases and pharmaceutical compositions comprising such compounds.

RELATED APPLICATIONS

[0001] This is a division of application Ser. No. 09/937,981, filed Oct.2, 2001, pending, which is a 371 of PCT/GB00/01252, filed Apr. 3, 2000which claims priority under 35 U.S.C. §119 from U.K. Application No9907571.5 filed Apr. 6, 1999.

BACKGROUND

[0002] The mammalian neurokinins comprise a class of peptideneurotransmitters which are found in the peripheral and central nervoussystems. The three principal neurokinins are Substance P (SP),Neurokinin A (NKA) and Neurokinin B (NKB). There are also N-terminallyextended forms of at least NKA. At least three receptor types are knownfor the three principal neurokinins. Based upon their relativeselectivities favoring the neurokinin agonists SP, NKA and NKB, thereceptors are classified as neurokinin-1 (NK₁), neurokinin-2 (NK₂) andneurokinin-3 (NK₃) receptors, respectively. In the periphery, SP and NKAare localized in C-afferent sensory neurons, which neurons arecharacterized by non-myelinated nerve endings known as C-fibers, and arereleased by selective depolarization of these neurons, or selectivestimulation of the C-fibers. C-Fibers are located in the airwayepithelium, and the tachykinins are known to cause profound effectswhich clearly parallel many of the symptoms observed in asthmatics. Theeffects of release or introduction of tachykinins in mammalian airwaysinclude bronchoconstriction, increased microvascular permeability,vasodilation, increased mucus secretion and activation of mast cells.Thus, the tachykinins are implicated in the pathophysiology and airwayhyperresponsiveness observed in asthmatics; and blockade of the actionof released tachykinins may be useful in the treatment of asthma andrelated conditions.

SUMMARY OF THE INVENTION

[0003] This invention relates to naphthalenecarboxamide compoundsN-substituted by an aminobutyl group, to pharmaceutical compositionscontaining such compounds, as well as to their uses and processes fortheir preparation. These compounds antagonize the pharmacologicalactions of the endogenous neuropeptide tachykinins known as neurokinins,particularly at the neurokinin-1 (NK₁) receptor. These compounds areuseful whenever such antagonism is desired. Thus, such compounds are ofvalue in the treatment of those diseases in which Substance P isimplicated, for example, in the treatment of asthma, anxiety,depression, emesis and related conditions.

[0004] The N-substituted naphthalenecarboxamide compounds of the presentinvention show a high degree of NK₁ receptor antagonist activity.

DETAILED DESCRIPTION

[0005] Accordingly the present invention provides the compounds of theformula (I):

R¹R²N—CH₂CH₂—CHAr¹—CH₂—NR³—CO—R⁴  (I)

[0006] wherein:

[0007] R¹ is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, aryl, C₁₋₆alkanoyl,C₁₋₆alkoxycarbonyl or arylcarbonyl; any of such groups being optionallysubstituted;

[0008] R² is hydrogen or C₁₋₆alkyl; or

[0009] R¹ or R² are joined to form an optionally substituted morpholinoring;

[0010] Ar¹ is phenyl mono- or di-substituted by halo;

[0011] R³ is hydrogen or C₁₋₆alkyl;

[0012] R⁴ is optionally substituted naphth-1-yl;

[0013] and pharmaceutically acceptable salts thereof.

[0014] When R¹ is optionally substituted C₂₋₆alkyl (for example ethyl orpropyl), C₂₋₆alkenyl (for example propenyl), C₁₋₆alkoxycarbonyl (forexample methoxycarbonyl or ethoxycarbonyl) and C₁₋₆alkanoyl (for exampleacetyl or propionyl), suitable substituents include halo for examplechloro, bromo or fluoro; nitro; cyano; hydroxy; C₁₋₆alkoxy for examplemethoxy or ethoxy; amino; C₁₋₆alkylamino for example methylamino orethylamino; di-C₁₋₆alkylamino for example dimethylamino;trifluoromethyl; carboxy; carbamoyl (NH₂CO—); C₁₋₆alkylcarbamoyl forexample methylcarbamoyl or ethylcarbamoyl; di-C₁₋₆alkylcarbamoyl forexample dimethyl-carbamoyl; C₁₋₆alkanoyl for example acetyl; mercapto;C₁₋₆alkylthio for example methylthio or ethylthio; C₁₋₆alkylsulphinylfor example methylsulphinyl or ethylsulphinyl; C₁₋₆alkylsulphonyl forexample methylsulphonyl or ethylsulphonyl; sulphamoyl;C₁₋₆alkoxycarbonyl for example methoxycarbonyl or ethoxycarbonyl;C₃₋₈cycloalkyl for example cyclopropyl, cyclopentyl or cyclohexyl;cyclobutyl, aryl; or heteroaryl.

[0015] When R¹ is substituted methyl, suitable substituents areC₃₋₈cycloalkyl for example cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl; aryl; or heteroaryl.

[0016] When R¹ is substituted aryl or arylcarbonyl (or when R¹ and R²together with the nitrogen atom to which they are joined form amorpholino ring) suitable substituents include those substituentsmentioned hereinabove (for other values of R¹), as well as C₁₋₆alkyl forexample methyl or ethyl, C₂₋₆alkenyl for example allyl or vinyl; orC₂₋₆alkynyl for example ethynyl.

[0017] “Aryl” in the terms “aryl” and “arylcarbonyl” means phenyl andnaphthyl.

[0018] Preferably R¹ is hydrogen, C₁₋₆alkyl optionally substituted byphenyl, C₂₋₆alkenyl, phenyl or benzoyl.

[0019] In particular R¹ is hydrogen, methyl, ethyl, n-propyl, isopropyl,propen-2-yl, phenyl or benzoyl.

[0020] Preferably R² is hydrogen or methyl.

[0021] In a particularly preferred aspect R¹ is methyl or ethyl and R²is hydrogen or methyl, for example R¹R²N— is methylamino.

[0022] In another preferred aspect R¹ and R² together with the nitrogenatom to which they are attached form a morpholino ring.

[0023] Favourably Ar¹ is phenyl di-substituted by chloro, for exampleAr¹ is 3,4-dichlorophenyl.

[0024] R³ is hydrogen or C₁₋₆alkyl for example methyl, ethyl orn-propyl. Preferably R³ is methyl.

[0025] R⁴ is optionally substituted naphth-1-yl. Suitable substituents,which are optional, for the naphth-1-yl group include hydroxy; cyano;nitro; trifluoromethoxy; trifluoromethyl; C₁₋₆alkylsulfonyl for examplemethylsulphonyl; halo for example chloro, bromo, fluoro or iodo;C₁₋₆alkoxy for example methoxy, ethoxy or propoxy; methylenedioxy(—OCH₂O—), C₁₋₆alkyl for example methyl or ethyl; C₂₋₆alkenyl forexample ethenyl, prop-1-enyl or prop-2-enyl; C₂₋₆alkynyl for exampleethynyl; carboxy, C₁₋₆alkoxy-carbonyl for example methoxycarbonyl;carbamoyl; C₁₋₆alkylcarbamoyl for example methylcarbamoyl orethylcarbamoyl; di-C₁₋₆alkylcarbamoyl for example di-methylcarbamoyl;C₁₋₆alkanoyl for example acetyl or propionyl; C₁₋₆alkanoylamino forexample acetylamino or propionylamino; aminosulfonyl; and C₁₋₆alkyl forexample methyl substituted by any of the hereinabove substituents.

[0026] Favourably the naphth-1-yl group is unsubstituted or issubstituted by up to three substituents. Preferred substituents for thenaphth-1-yl group include cyano; nitro; C₁₋₆alkylsulfonyl for examplemethylsulphonyl; halo for example chloro, bromo, fluoro or iodo;C₁₋₆alkoxy for example methoxy, ethoxy, n-propoxy or isopropoxy;methylenedioxy (—OCH₂O—); C₁₋₆alkyl for example methyl or ethyl;C₂₋₆alkenyl for example prop-2-enyl; C₂₋₆alkynyl for example ethynyl;carboxy, carbamoyl; C₁₋₆alkyl-carbamoyl for example methylcarbamoyl;di-C₁₋₆alkylcarbamoyl for example di-methylcarbamoyl; C₁₋₆alkanoyl forexample acetyl; C₁₋₆alkanoylamino for example acetylamino;aminosulfonyl; and cyanoC₁₋₆alkyl for example cyanomethyl.

[0027] More preferred substitutents for the naphth--yl group are cyano,methoxy, ethoxy, isopropoxy, fluoro, bromo, chloro, iodo, nitro,cyanomethyl, carboxy, carbamoyl, ethynyl, methyl, ethyl,dimethylcarbamoyl, methylsulfonyl, aminosulfonyl, prop-2-enyl, acetyland acetylamino.

[0028] In particular the naphth-1-yl group may be substituted by up totwo substituents selected from cyano, methoxy, ethyl, fluoro and nitro.A particularly preferred substitution pattern for the naphth-1-yl groupis 3-cyano. A further particularly preferred substitution pattern is3-cyano, 2-methoxy. Another particularly preferred substitution patternis 2,3-dimethoxy. Another particularly preferred substitution pattern is3-cyano, 2-ethyl.

[0029] The compounds of the present invention possess a chiral centre,at —CHAr¹— and possibly in the optional substituents. The presentinvention covers all isomers, diastereoisomers and mixtures thereof thatantagonise NK₁ receptors.

[0030] The preferred configuration at —CHAr¹— is shown in formula (Ia)hereinbelow:

[0031] Thus a preferred class of compounds of the present invention isthat of the formula (Ia) wherein R¹ is hydrogen, methyl or ethyl; R² ishydrogen or methyl; R³ is methyl; Ar¹ is 3,4-dichlorophenyl; and R⁴ isnaphth-1-yl optionally substituted by up to two substituents selectedfrom cyano, methoxy, ethyl, fluoro and nitro.

[0032] Particular compounds of the invention are those of the Examples.

[0033] Pharmaceutically acceptable salts of the compounds of the formula(I) include those made with inorganic or organic acids which afford aphysiologically acceptable anion, such as with, for example,hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic,sulfamic, para-toluenesulfonic, acetic, citric, lactic, tartaric,malonic, fumaric, ethanesulfonic, benzenesulfonic, cyclohexylsulfamic,salicyclic and quinic acids.

[0034] In order to use a compound of the formula (I) or apharmaceutically acceptable salt thereof for the therapeutic treatment(including prophylactic treatment) of mammals including humans, it isnormally formulated in accordance with standard pharmaceutical practiceas a pharmaceutical composition.

[0035] Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula (I)or a pharmaceutically acceptable salt and pharmaceutically acceptablecarrier.

[0036] The pharmaceutical compositions of this invention may beadministered in standard manner for the disease condition that it isdesired to treat, for example by oral, topical, parenteral, buccal,nasal, vaginal or rectal administration or by inhalation orinsufflation. For these purposes the compounds of this invention may beformulated by means known in the art into the form of, for example,tablets, capsules, aqueous or oily solutions, suspensions, emulsions,creams, ointments, gels, nasal sprays, suppositories, finely dividedpowders or aerosols or nebulisers for inhalation, and for parenteral use(including intravenous, intramuscular or infusion) sterile aqueous oroily solutions or suspensions or sterile emulsions.

[0037] In addition to the compounds of the present invention thepharmaceutical composition of this invention may also contain, or beco-administered (simultaneously or sequentially) with, one or morepharmacological agents of value in treating one or more diseaseconditions referred to herein.

[0038] The pharmaceutical compositions of this invention will normallybe administered to humans so that, for example, a daily dose of 0.01 to25 mg/kg body weight (and preferably of 0.1 to 5 mg/kg body weight) isreceived. This daily dose may be given in divided doses as necessary,the precise amount of the compound received and the route ofadministration depending on the weight, age and sex of the patient beingtreated and on the particular disease condition being treated accordingto principles known in the art.

[0039] Typically unit dosage forms will contain about 1 mg to 500 mg ofa compound of this invention. For example a tablet or capsule for oraladministration may conveniently contain up to 250 mg (and typically 5 to100 mg) of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof. In another example, for administration byinhalation, a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof may be administered in a daily dosage range of 5to 100 mg, in a single dose or divided into two to four daily doses. Ina further example, for administration by intravenous or intramuscularinjection or infusion, a sterile solution or suspension containing up to10% w/w (and typically 5% w/w) of a compound of the formula (I) or apharmaceutically acceptable salt thereof may be used.

[0040] Therefore in a further aspect, the present invention provides acompound of the formula (I) or a pharmaceutically acceptable saltthereof for use in a method of therapeutic treatment of the human oranimal body.

[0041] In yet a further aspect the present invention provides a methodof treating a disease condition wherein antagonism of the NK₁ receptoris beneficial which comprises administering to a warm-blooded animal aneffective amount of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof. The present invention also provides the use ofa compound of the formula (I) or a pharmaceutically acceptable saltthereof in the preparation of a medicament for use in a diseasecondition wherein antagonism of the NK₁ receptor is beneficial.

[0042] The compounds of the formula (I) and their pharmaceuticallyacceptable salts may be made by processes as described and exemplifiedherein and by processes similar thereto and by processes known in thechemical art. If not commercially available, starting materials forthese processes may be made by procedures which are selected from thechemical art using techniques which are similar or analogous to thesynthesis of known compounds.

[0043] In another aspect the present invention provides a process forpreparing a compound of the formula (I) or a pharmaceutically acceptablesalt thereof which process comprises:

[0044] a) reacting a compound of the formula (III):

OHC—CH₂—CHAr¹—CH₂—NR³—COR⁴  (III)

[0045] wherein Ar¹, R³ and R⁴ are as hereinbefore defined with acompound of the formula R¹R²NH; or

[0046] b) reacting a compound of the formula (IV):

R¹R²N—CH₂—CH₂—CHAr¹—CH₂—NHR³  (IV)

[0047] wherein R¹, R², R³ and Ar¹ are as hereinbefore defined with acompound of the formula L—CO—R⁴ wherein L is a leaving group;

[0048] wherein any functional group is protected, if necessary, and

[0049] i) removing any protecting group;

[0050] ii) optionally converting a compound of the formula (I) intoanother compound of the formula (I);

[0051] iii) optionally forming a pharmaceutically acceptable salt.

[0052] Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled chemist asappropriate for the protection of the group in question, and may beintroduced and removed by conventional methods; see for exampleProtecting Groups in Organic Chemistry; Theodora W. Greene. Methods ofremoval are chosen so as to effect removal of the protecting group withminimum disturbance of groups elsewhere in the molecule.

[0053] It will also be appreciated that certain of the various optionalsubstituents in the compounds of the formula (I) may be introduced bystandard aromatic substitution reactions or generated by conventionalfunctional group modifications either prior to or immediately followingthe processes described hereinabove. The reagents and reactionconditions for such procedures are well known in the chemical art.

[0054] Pharmaceutically acceptable salts may be prepared from thecorresponding acid in conventional manner. Non-pharmaceuticallyacceptable salts may be useful as intermediates and as such are anotheraspect of the present invention.

[0055] It is well known in the art how to prepare optically-active forms(for example, by resolution of the racemic form or by synthesis fromoptically-active starting materials) and how to determine the NK₁antagonist properties by the standard tests known in the art and thosedescribed hereinafter.

[0056] The compounds of the formulae (III) and R¹R²NH are reacted underconditions of reductive amination. The reaction is typically performedat a non-extreme temperature, for example 0-100° C., more suitably atambient temperature, in a substantially inert solvent for exampledichloromethane or methanol. Typical reducing agents includeborohydrides such as sodium cyanoborohydride. The compounds of theformula R¹R²NH are known or may be prepared in conventional manner. Thecompounds of the formula (III) may be prepared from the correspondingalcohol, which itself may be prepared by N-acylation of thecorresponding substituted hydroxybutylamine.

[0057] The compounds of the formula (IV) and LCOR⁴ are reacted underconventional acylation conditions wherein LCOR⁴ is an acid or activatedacid derivative such as an acid chloride. The compounds of the formula(IV) may be prepared by reacting a compound of the formula (V):

OHC—CH₂—CHAr¹—CH₂NHR³  (V)

[0058] wherein Ar¹ and R³ are as hereinbefore defined, with R¹R²NH underreductive amination conditions, with functional groups being protectedas necessary. For example, when it is desired to prepare a compound ofthe formula (IV) when R³ is hydrogen, the —NHR³ function of the compoundof the formula (V) may be protected as a phthalimido group, removalconventionally such as by hydrazinolysis. The compounds of the formula(V) are known or may be prepared in conventional manner for example fromthe corresponding substituted hydroxybutylamine.

[0059] The compounds of the formula (I) may be converted to othercompounds of the formula (I), for example a compound of the formula (I)wherein R¹ is hydrogen may be acylated in conventional manner to formthe corresponding compound wherein R¹ is arylcarbonyl oralkanoylcarbonyl.

[0060] The following biological test methods, data and Examples serve toillustrate and further describe the invention.

[0061] he utility of a compound of the invention or a pharmaceuticallyacceptable salt thereof (hereinafter, collectively referred to as a“Compound”) may be demonstrated by standard tests and clinical studies,including those disclosed in the publications described below.

[0062] SP Receptor Binding Assay (Test A)

[0063] The ability of a Compound of the invention to antagonize thebinding of SP at the NK₁ receptor may be demonstrated using an assayusing the human NK₁ receptor expressed in Mouse Erythroleukemia (MEL)cells. The human NK₁ receptor was isolated and characterized asdescribed in: B. Hopkins, et al. “Isolation and characterization of thehuman lung NK₁ receptor cDNA” Biochem. Biophys. Res. Comm., 1991, 180,1110-1117; and the NK₁ receptor was expressed in Mouse Erythroleukemia(MEL) cells using a procedure similar to that described in Aharony, D.,et al. “Isolation and Pharmacological Characterization of a HamsterNeurokinin A Receptor cDNA” Molecular Pharmacology, 1994, 45, 9-19.

[0064] Rabbit Pulmonary Artery: NK₁ in vitro Functional Assay (Test C)

[0065] The ability of a Compound of the invention to antagonize theaction of the agonist Ac—[Arg⁶, Sar⁹, Met(O2)¹¹] Substance P (6-11),ASMSP, in a pulmonary tissue may be demonstrated according to publishedmethods; J. Pharmacol. Exp. Ther. 1993, 267, 1168; Buckner C K, LiberatiN, Dea D, Lengel D, Stinson-Fisher C, Campbell J, Miller S, Shenvi A,Krell R D.

[0066] Male New Zealand white rabbits are euthanized via i.v. injectioninto an ear vein with 60 mg/kg Nembutal (50 mg/ml). Preceding theNembutal into the vein is Heparin (1000 units/ml) at 0.0025 ml/kg foranticoagulant purposes. The chest cavity is opened from the top of therib cage to the sternum and the heart, lungs and part of the trachea areremoved. The pulmonary arteries are isolated from the rest of thetissues and cut in half to serve as pairs.

[0067] The segments are suspended between stainless steel stirrups, soas not to remove any of the endothelium, and placed in water-jacketed(37.0° C.) tissue baths containing physiological salt solution of thefollowing composition (mM): NaCl, 118.0; KCl, 4.7; CaCl₂, 1.8; MgCl₂,0.54; NaH₂PO₄, 1.0; NaHCO₃, 25.0; glucose, 11.0; indomethacin, 0.005(toinhibit cyclooxygenase); and dl-Propranolol, 0.001(to block βreceptors); gassed continuously with 95% O₂-5% CO₂. Responses aremeasured on a Grass polygraph via Grass FT-03 transducers and theelectrical signals (data) acquired using a Mi² software/hardware systemfor subsequent conversion to measures of relaxation.

[0068] Initial tension placed on each tissue is 2 grams, which ismaintained throughout the 1.0 hour equilibration period. Tissues arewashed with the physiological salt solution at 15 minute intervals. Atthe 30 and 45 minute wash the following treatments are added: 1×10⁻⁶MThiorphan (to block E.C.3.4.24.11), 3×10⁻⁸M(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-N-methylbenzamide(to block NK₂ receptors), and the given concentration of the Compoundbeing tested. At the end of the 1.0 hour equilibration, 1×10⁻⁶ML-Phenylephrine hydrochloride is added for 1.0 hour. At the end of the1.0 hour, a dose relaxation curve to ASMSP is done. Each tissue istreated as a individual and is considered finished when it fails torelax further for 2 consecutive doses. When this section of the protocolis complete, 1×10⁻¹M Papaverine is added for maximum relaxation.

[0069] For non-competitive antagonists, the percent inhibition ofrelaxation is determined at a given concentration of the antagonist.Percent inhibition is determined when a tested Compound produces astatistically significant (p<0.05) reduction of the total relaxationwhich is calculated using the total relaxation as a percent of thecontrol value. Potencies of competitive Compounds are determined bycalculating the apparent dissociation constants (K_(B)) for eachconcentration tested using the standard equation:

K_(B)=[antagonist]/(dose ratio −1)

[0070] where dose ratio=antilog[(agonist−log molar EC₅₀ withoutCompound)−(−log molar EC₅₀ with Compound)]. The K_(B) values may beconverted to the negative logarithms and expressed as −log molar K_(B)(i.e. pK_(B)). For this evaluation, complete concentration-responsecurves for agonist obtained in the absence and presence of the Compoundtested using paired pulmonary artery rings. The potency of the agonistis determined at 50% of its own maximum relaxation in each curve. TheEC₅₀ values are converted to negative logarithms and expressed as −logmolar EC₅₀.

[0071] NK₁ in vivo Functional Assay (Test E)

[0072] The activity of a compound as an antagonist of NK₁ receptors alsomay be demonstrated in vivo in laboratory animals as described in:Buckner et al. “Differential Blockade by Tachykinin NK₁ and NK₂ ReceptorAntagonists of Bronchoconstriction Induced by Direct-Acting Agonists andthe Indirect-Acting Mimetics Capsaicin, Serotonin and 2-Methyl-Serotoninin the Anesthetized Guinea Pig.” J. Pharm. Exp. Ther.,1993, Vol 267(3),pp1168-1175.

[0073] Results of testing of representative compounds of the presentinvention by the above methods are presented in the Table I: TABLE 1Example NK₁ pKb (Test C) 4 8.3 6 8.7

[0074] Clinical Studies

[0075] Clinical studies to demonstrate the efficacy of a Compound of theinvention may be carried out using standard methods.

[0076] The Tests provide evidence of general antagonism of SP. SP hasbeen implicated in the pathology of numerous diseases including:rheumatoid arthritis, Alzheimer's disease, cancer, schizophrenia,oedema, allergic rhinitis, inflammation, pain,gastrointestinal-hypermotility, gastric asthma, gastroesphageal reflux,anxiety, emesis, Huntington's Disease, psychoses including depression,hypertension, migraine and urticaria.

[0077] Accordingly, one feature of the invention is the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof inthe treatment of a disease in a human or other mammal in need thereof inwhich SP is implicated and antagonism of its action is desired.

[0078] There is a possible role for Substance P antagonists in thetreatment of depression. Accordingly another feature of the invention isthe use of a compound of formula (I) or a pharmaceutically acceptablesalt thereof in the treatment of depression in a human or other mammalin need thereof.

[0079] Because of the range of effects attributable to the actions ofSP, compounds which are capable of blocking their actions may also beuseful as tools for further evaluating the biological actions of otherneurotransmitters in the Tachykinin family. As a result, another featureof the invention is provided by the use of a compound of Formula I or asalt thereof as a pharmacological standard for the development andstandardization of new disease models or assays for use in developingnew therapeutic agents for treating diseases in which SP are implicatedor for assays for their diagnosis.

[0080] The invention is illustrated by the following non-limitingexamples, in which, where applicable and unless stated otherwise:

[0081] (i) operations were carried out at room or ambient temperature,that is, at a temperature in the range of 18-25° C.;

[0082] (ii) organic solutions were dried over anhydrous magnesiumsulfate; evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 pascals; 4.5-30 mm Hg) witha bath temperature of up to 60° C.;

[0083] (iii) melting points are uncorrected;

[0084] (iv) final products had satisfactory proton nuclear magneticresonance (NMR) spectra;

[0085] (v) Mass spectra (MS) were run using an automated system withatmospheric pressure chemical ionization (APCI). Generally, only spectrawhere parent masses are observed are reported.

[0086] Abbreviations: CO, carbon monoxide; DCM, methylene chloride; DMF,N,N-dimethylformamide; DMSO, dimethyl sulfoxide; Et₂O, diethyl ether;EtOAc, ethyl acetate; h, hour(s); min, minutes; NMR, nuclear magneticresonance; psi, pounds per square inch; THF, tetrahydrofuran.

[0087] Standard acylation refers to the typical procedure in which anacid chloride (1-1.2 equivalents) is added to a stirred solution of anamine (1-1.2 equivalents) and triethylamine (2 equivalents) in DCM.After 1-16 h the reaction is optionally concentrated, dissolved in DCM,and washed with saturated sodium bicarbonate and then purified bychromatography.

[0088] Standard reductive amination refers to the typical procedure inwhich a solution of an amine (1-1.2 equivalents), an aldehyde (1-1.2equivalents) and acetic acid (2 equivalents) are stirred in methanol for5 to 60 minutes before adding NaBH₃CN (1.7 equivalents). After 1-16 hthe reaction is optionally concentrated, dissolved in DCM, and washedwith saturated sodium bicarbonate and then purified by chromatography.

[0089] Final compounds were converted to the citrate salt. The free basewas combined with citric acid (1.0 equivalents) in methanol,concentrated under reduced pressure and dried under vacuum (25-50° C.).

EXAMPLE 1

[0090]N-[(S)-2-(3,4-Dichloropheny)-4-(phenylamino)butyl]-N-methyl-2-methoxy-3-cyano-1-naphthamide

[0091]N-[(S)-2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methyl-2-methoxy-3-cyano-1-naphthamidewas reacted with aniline under standard reductive amination conditionsto give the title compound which was converted to the citrate salt. ¹HNMR (300 MHz, DMSO-d₆) δ 8.64-8.61 (m), 8.07-7.98 (m), 7.79-7.55 (m),7.51-7.47 (m), 7.37-7.32 (t), 7.08-7.00 (m), 6.53-6.49 (m), 6.31-6.28(d), 4.60-4.50 (t), 4.07-3.96 (m), 3.92 (s), 3.90-3.78 (m), 3.86 (s),3.45-3.11 (m), 3.00-2.88 (m), 2.79 (s), 2.73 (s), 2.68 (s), 2.56-2.44(m), 2.03-1.88 (m); MS APCI, m/z=532 (M⁺).

[0092]N-[(S)-2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methyl-2-methoxy-3-cyano-1-naphthamide was Prepared as Follows:

[0093] (a) 3-Hydroxy-4-iodo-2-naphthoic Acid.

[0094] A mixture of NaOH (2.12 g) in methanol (100 mL) was stirred untilthe solution was homogeneous. Sodium iodide (3.98 g) and3-hydroxy-2-naphthoic acid (5.00 g) were added and allowed to stir for30 min. The resulting suspension was cooled to 0° C. and a 5.25% (w/v)aqueous solution of sodium hypochlorite was added dropwise and stirringcontinued for 1 h. Saturated sodium thiosulfate (25 mL) was added andafter 5 min the solution was acidified to pH 2 by addition of 6N HClresulting in the formation of a yellow precipitate which was filteredand washed with water (50 mL). The precipitate was transferred to around-bottomed flask, dissolved in methanol (70 mL) and toluene (100mL), concentrated, redissolved in methanol (70 mL), concentrated,redissolved again in methanol (70 mL) and toluene (100 mL) andconcentrated to afford the product as a yellow solid (6.26 g). MS m/z313 (M−1). ¹H NMR (DMSO-d₆): δ 12.41 (broad, 1H), 8.63 (s, 1H),8.05-7.97 (m, 2H), 7.70 (m, 1H), 7.42 (m, 1H).

[0095] (b) Methyl 3-methoxy-4-iodo-2-naphthoate.

[0096] A solution of 3-hydroxy-4-iodo-2-naphthoic acid (8.0 g), dimethylsulfate (8.03 g), powdered potassium carbonate (8.80 g), and dry acetone(150 mL) was heated under reflux for 18 h. The solution was cooled toroom temperature, triethylamine (15 mL) was added, and stirringcontinued for 30 min. The solution was filtered through a pad ofDiatomaceous earth and washed with dry acetone (50 mL). The filtrate wasconcentrated to a yellow oil, diluted with EtOAc, and washedsuccessively with 1N HCl (100 mL), saturated aqueous sodium bicarbonate(100 mL), and brine (100 mL). The organic phase was dried (sodiumsulfate), filtered, concentrated, and purified by chromatography (0-10%EtOAc in hexanes) to afford the product as a yellow oil (5.53 g). ¹H NMR(DMSO-d₆) δ 8.47 (s, 1H), 8.09 (m, 2H), 7.74 (m, 1H), 7.61 (m, 1H), 3.94(s, 3H), 3.87 (s, 3H).

[0097] (c) 1-Iodo-2-methoxy-3-cyanonaphthalene.

[0098] Based on the procedure of Wood, J L; Khatri, N A; Weinreb, S M;Tetrahedron Lett; 51, 4907 (1979), methyl 3-methoxy-4-iodo-2-naphthoate(5.0 g) was suspended in xylenes (100 mL), cooled to 0° C.,dimethylaluminum amide solution (approximately 37 mmol) was added andthe solution heated under reflux for 2.5 h. The solution was then cooledto 0° C. and acidified to pH 2 by addition of 1N HCl and extracted withEtOAc (3×100 mL).

[0099] The combined EtOAc extracts were washed with saturated aqueoussodium bicarbonate (150 mL) and brine (150 mL), dried (sodium sulfate),filtered, concentrated, and purified by chromatography (1:1 EtOAc:DCM,then 10-20% EtOAc in DCM) to afford the product as a white solid (3.29g). ¹H NMR (DMSO-d₆): δ 8.69 (s, 1H), 8.24-8.04 (m, 2H), 7.91-7.81 (m,1H), 7.76-7.65 (m, 1H), 3.99 (s, 3H); MS m/z 311 (M+H).

[0100] (d) Methyl 2-methoxy-3-cyano-1-naphthoate.

[0101] Through a suspension of 1-iodo-2-methoxy-3-cyanonaphthalene(0.250 g), Pd(OAc)₂ (0.018 g), triethylamine (0.081 g) and methanol (20mL) was bubbled carbon monoxide for 25 min, then stirred at 70° C. undercarbon monoxide (1 atm) for 18 h. The cooled solution was filtered,rinsed with methanol (20 mL) and DCM (20 mL), concentrated, preadsorbedonto silica (1 g) and purified by chromatography (0-10% EtOAc inhexanes) to afford the product as a white solid (0.113 g). ¹H NMR(DMSO-d₆): δ 8.78 (s, 1H), 8.12-8.09 (m, 1H), 7.84-7.78 (m, 2H),7.70-7.63 (m, 1H), 4.02-4.01 (m, 6H); IR (cm⁻¹): 2228, 1724, 1296, 1236,1208, 1017.

[0102] (e) 2-Methoxy-3-cyano-1-naphthoic Acid.

[0103] A solution of methyl 2-methoxy-3-cyano-1-naphthoate (0.113 g),LiOH.H₂O (0.0196 g), THF (3 mL), water (1 mL) and methanol (1 mL) wasstirred overnight at room temperature. The solution was diluted withsaturated sodium bicarbonate and extracted with Et₂O. The aqueous layerwas acidified to pH 2 by addition of 1N HCl and extracted with Et₂O. Theorganic layer was washed with water (30 mL) and brine (40 mL), dried(sodium sulfate), filtered, and concentrated to a white solid. ¹H NMR(DMSO-d₆): δ 14.06 (broad, 1H), 8.08-8.02 (m, 1H), 7.83-7.76 (m, 2H),7.69-7.63 (m, 1H), 4.02 (s, 3H); MS m/z: 226 (M−1).

[0104] (f) 2-Methoxy-3-cyano-1-naphthoyl Chloride.

[0105] The carboxylic acid was converted to the corresponding acidchloride by reaction with oxalyl chloride in DCM with a catalytic amountof DMF. After concentrating the reaction mixture to dryness, the acidchloride was used without purification.

[0106] (g)N-[2-(S)-(3,4-Dichlorophenyl)-4-hydroxybutyl]-N-methyl-3-cyano-2-methoxy-1-naphthamide.

[0107] A solution ofN-[(S)-2-(3,4-Dichlorophenyl)-4-hydroxybutyl]-N-methylamine (Miller, S.C., WO 9512577) in DCM was combined with 10% aqueous sodium bicarbonatesolution. The mixture was cooled to 0° C. and a solution of3-cyano-2-methoxy-1-naphthoyl chloride in DCM was added dropwise over 30min. After stirring overnight at room temperature, the organic phase wasconcentrated and purified by column chromatography to affordN-[2-(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methyl-3-cyano-2-methoxy-1-naphthamide.¹H NMR (300 MHz, DMSO-d₆) δ 9.70-9.64 (m), 8.67-8.57 (m), 8.07-7.97 (m),7.80 (s), 7.72-7.55 (m), 7.52-7.48 (m), 7.40-7.33 (m), 7.12-7.10 (d),7.04-7.02 (d), 6.87-6.83 (m), 6.37-6.29 (d), 4.53-4.44 (t), 4.11-4.00(m), 3.94 (s), 3.92 (s), 3.91-3.73 (m), 3.71 (s), 3.45-3.38 (m), 3.33(s), 3.14 (s), 2.97-2.95 (d), 2.63 (s), 2.60 (s); MS APCI, m/z 455 (M⁺).This compound was characterized as a mixture of atropoisomers.

[0108] (h)N-[2-(S)-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methyl-3-cyano-2-methoxy-1-naphthamide.

[0109] The alcohol from (g) was oxidized using oxalyl chloride and DMSOunder standard Swern conditions to afford the aldehyde. ¹H NMR (300 MHz,DMSO-d₆) δ 9.70-9.64(m), 8.67-8.57 (m), 8.07-7.97 (m), 7.80 (s),7.72-7.55 (m), 7.52-7.48 (m), 7.40-7.33 (m), 7.12-7.10 (d), 7.04-7.02(d), 6.87-6.83 (m), 6.37-6.29 (d), 4.53-4.44 (t), 4.11-4.00 (m), 3.94(s), 3.92 (s), 3.91-3.73 (m), 3.71 (s), 3.45-3.38 (m), 3.33 (s), 3.14(s), 2.97-2.95 (d), 2.63 (s), 2.60 (s); MS APCI, m/z=455 (M⁺). Thiscompound was characterized as a mixture of atropoisomers.

EXAMPLE 2-6

[0110] For examples 2, 3, 4, and 6,N-[(S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methyl-2-methoxy-3-cyano-1-naphthamidewas reacted with the appropriate amine under standard reductiveamination conditions. Example 5 was prepared in like manner except that,N-[(S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methyl-2-methoxy-3-cyano-1-naphthamidewas replaced withN-[(S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methyl-3-cyano-1-naphthamide.All compounds were converted to the corresponding citrate salts.

Example 2

[0111]

[0112]¹H NMR (300 MHz, DMSO-d₆) δ 8.65-8.63 (m), 8.12-7.98 (m),7.77-7.55 (m), 7.51-7.46 (t), 7.39-7.34 (t), 7.07-7.02 (m), 6.89-6.80(m), 6.32-6.29 (d), 5.87-5.76 (m), 5.39-5.21 (m), 4.55-4.47 (t), 3.94(s), 3.93-3.77 (m), 3.70 (s), 3.64-3.17 (m), 3.11-2.74 (m), 2.67-2.47(m), 2.38-2.14 (m), 2.00 (bs), 1.35-1.07 (m); MS APCI, m/z=510 (M⁺).

Example 3

[0113]

[0114]¹H NMR (300 MHz, DMSO-d₆) δ 8.65-8.63 (m), 8.08-7.97 (m),7.71-7.69 (m), 7.67-7.49 (m), 7.40-7.37 (m), 7.31-7.22 (m), 7.03-7.00(d), 6.89-6.85 (d), 6.77-6.74 (d), 6.31-6.29 (d), 4.53-4.46 (t),4.01-3.96 (m), 3.94 (s), 3.92 (s), 3.88-3.76 (m), 3.68 (s), 3.47-3.16(m), 3.10 (s), 3.01 (s), 2.70-2.45 (m), 2.34 (bs), 2.06-1.96 (m); MSAPCI, m/z=560 (M⁺).

Example 4

[0115]

[0116]¹H NMR (300 MHz, DMSO-d₆, 373 K) δ 8.6-8.7 (m), 7.9-8.1(m),7.3-7.8 (m), 6.8-7.1(m), 6.3 (d), 4.5 (t), 3.0-4.0 (m), 2.6-2.7 (m),1.8-2.4 (m); MS APCI, m/z=526 (M⁺); analysis calculated forC₂₈H₂₉Cl₂N₃O₃, 1.0 citric acid, 1.0 water, C, 55.44, H, 5.34, N, 5.70,found C, 55.57, H, 5.12, N, 5.65.

Example 5

[0117]

[0118] Morpholine is the amine, exceptN-[2-(S)-(3,4-dichlorophenyl)-4-oxobutyl]-N-methyl-3-cyano-1-naphthamidewas used in place ofN-[2-(S)-(3,4-dichlorophenyl)-4-oxobutyl]-N-methyl-3-cyano-2-methoxy-1-naphthamide.¹H NMR (300 MHz, DMSO-d₆, 373 K) δ 8.4(s), 8.0 (d), 7.2-7.7 (m), 3.8(s), 3.5 (m), 3.2 (s), 2.6-2.8 (m), 2.2-2.4 (m), 1.6-2.0 (m); MS APCI,m/z=496 (M⁺); analysis calculated for C₂₇H₂₇Cl₂N₃O₂, 1.0 citric acid,1.0 water, C, 56.10, H, 5.28, N, 5.95, found C, 56.40, H, 5.07, N, 5.95.

Example 6

[0119]

[0120]¹H NMR (300 MHz, DMSO-d₆) δ 8.64 (d), 8.04 (m), 7.79-7.56 (m),7.49 (d), 7.40-7.32 (m), 7.08 (m), 6.84 (m), 6.32 (d), 4.50 (t), 3.95(m), 3.89-3.75 (m), 3.71 (s), 3.49 (m), 3.32 (m), 3.14 (m), 3.07 (s),2.95 (m), 2.64 (s), 2.58 (s), 2.54 (s), 2.50 (s), 2.45 (m), 2.38 (m),2.18 (m), 2.08-1.98 (m); MS APCI, m/z=484 (M⁺).

[0121] For Example 5, the intermediateN-[2-(S)-(3,4-dichlorophenyl)-4-oxobutyl]-N-methyl-3-cyano-1-naphthamidewas prepared as follows:

[0122] (i) 3-Cyano-1-naphthoyl Chloride.

[0123] Using the procedure of Rule, H G and Thompson, S B; J. Chem. Soc.1764-1767 (1937), 1,8-naphthalic anhydride was brominated and convertedto 3-bromo-1-naphthoic acid. This was esterified to methyl3-bromo-1-naphthoate according to the following procedure.3-Bromo-1-naphthoic acid (103.0 g, 410 mmol) was dissolved in DCM (1250mL) and the solution cooled to 0° C. Oxalyl chloride (67.5 g, 532 mmol)was added in one portion followed by a catalytic amount of DMF (1.5 mL),and the resulting solution allowed to warm to ambient temperature andstir for 4 hours. The mixture was evaporated in vacuo, and the residueconcentrated a second time from toluene. The resultant acid chloride wasdissolved in methanol (1250 mL) and stirred at ambient temperature for18 h. The mixture was evaporated in vacuo, and the residue purified bychromatography (eluent: DCM:hexanes 1:3) to provide methyl3-bromo-1-naphthoate as a white solid (106.9 g, 98%). ¹H-NMR (CDCl₃) δ4.01 (s, 3H, CO₂CH₃); 7.50-7.69 (m, 2H, aromatic); 7.78-7.87 (d, 1H,aromatic); 8.18 (s, 1H, aromatic); 8.25 (s, 1H, aromatic); 8.80-8.94 (d,1H, aromatic). Using the procedure of Dewar, J S and Grisdale, P J; J.Amer. Chem. Soc., 84, 3541-3546 (1962), methyl-3-bromo-1-naphthoate wasconverted to methyl 3-cyano-1-naphthoate and then saponified (LiOH) toafford 3-cyano-1-naphthoic acid. 3-Cyano-1-naphthoic acid (15.9 g, 80.6mmol) was suspended in DCM (450 mL). To the stirred mixture was addedoxalyl chloride (12.8 g, 100 mmol) in one portion followed by acatalytic amount (5 drops) of DMF. The mixture was stirred for 5 hoursat room temperature giving a clear solution. The mixture wasconcentrated in vacuo, and the residue concentrated twice from tolueneto provide the acid chloride as a light yellow solid (17.4 g,quantitative). ¹H-NMR (300 MHz, d₆ acetone) δ 7.86-7.91 (t, 1H,aromatic); 7.98-8.04 (t, 1H, aromatic); 8.28-8.32 (d, 1H, aromatic);8.66-8.72 (d, 1H, aromatic); 8.80 (s, 1H, aromatic); 8.93 (s, 1H,aromatic).

[0124] (ii)N-[(S)-2-(3,4-Dichlorophenyl)-4-hydroxybutyl]-N-methyl-3-cyano-1-naphthamide.

[0125] (S)-2-(3,4-Dichlorophenyl)-4-hydroxybutylamine (20.8 g, 83.8mmol) was dissolved in DCM (700 mL). To the stirred solution was added10% aqueous sodium bicarbonate (300 mL), and the mixture cooled to 0° C.A solution of 3-cyano-1-naphthoyl chloride (17.4 g, 80.6 mmol) in DCM(300 mL) was added dropwise over 30 minutes. The mixture was thenallowed to warm to ambient temperature and stir for 20 h. The layerswere separated, and the aqueous phase washed with DCM (300 mL). Thecombined organic layers were dried (Na₂SO₄), filtered, and evaporated invacuo to give a white foam. Purification by chromatography (silica gel;0-25% acetonitrile in DCM) provided the desired product as a white foam(27.0 g, 78%). ¹H-NMR (DMSO-d₆) δ 1.46-1.60 (m, 1H, CH); 1.77-1.91 (m,3H, CH); 4.38-4.41 (t, 1H, CH); 4.54-4.57 (t, 2H, CH); 6.43 (broad, 1H,OH); 6.84-7.26 (m, 2H, aromatic); 7.44-7.54 (m, 3H, aromatic); 7.57-7.80(m, 7H, aromatic); 8.04-8.33 (m, 2H, aromatic); 8.61 (s, 1H, aromatic).

[0126] (iii)N-[(S)-2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methyl-3-cyano-1-naphthamide.

[0127] A solution of oxalyl chloride (15.9 g, 125.4 mmol) dissolved inDCM (350 mL) was cooled to −78° C. DMSO (19.6 g, 251 mmol) was addeddropwise over 10 minutes while maintaining the temperature of thereaction mixture below −70° C. The mixture was stirred for 30 min at−78° C. A solution ofN-[(S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methyl-3-cyano-1-naphthamide(26.8 g, 62.7 mmol) was dissolved in DCM (350 mL) and added dropwiseover 30 min while maintaining the temperature of the mixture below −70°C. The mixture was allowed to stir for one h at −78° C., then warmed to−50° C. and stirred for another 30 minutes. The mixture was cooled to−78° C. and a solution of triethylamine (25.4 g, 251 mmol) dissolved inDCM (70 mL) was added dropwise over 10 min. The mixture was then allowedto warm gradually to ambient temperature and stir for 20 hours. Themixture was then washed with 0.5N hydrochloric acid (2×250 mL), water(250 mL), and saturated sodium bicarbonate (250 mL). The organic layerwas dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue waspurified by chromatography (silica gel; 0-20% Et₂O in DCM) to providethe desired product as a light yellow foam (26.0 g, 97%). MS: 425 (M+H).¹H-NMR (DMSO-d₆) δ 2.63 (bs, 3H, NCH₃); 2.99-3.93 (m, 5H, CH); 6.91-7.15(m, 1H, aromatic); 7.33-7.81 (m, 6H, aromatic); 8.62 (s, 1H, aromatic);9.45 and 9.73 (singlets, 1H total, CHO).

EXAMPLE 7

[0128] The allyl group from the product of Example 2 was removed usingPd(dba)₂ (i.e. bis(dibenzylideneacetone)palladium) in the presence of2-mercaptobenzoic acid according to the procedure of Lemaire-Andoire etal., Tetr. Lett. 1995, 36, 1267, to give the corresponding methylamine.

[0129]¹H NMR (300 MHz, DMSO-d₆) δ 8.66-8.64 (m), 8.08-7.96 (m),7.80-7.56 (m), 7.51-7.47 (m), 7.40-7.35 (m), 7.07-7.05 (m), 6.85-6.79(m), 6.35-6.32 (d), 4.54-4.45 (t), 3.95 (s), 3.92 (s), 3.90-3.70 (m),3.72 (s), 3.50-3.10 (m), 2.86-2.50 (m), 2.44-1.69 (m); MS APCI, m/z=470(M⁺).

EXAMPLE 8

[0130] A solution of the product from Example 7 in DCM was stirred witha 10% solution of sodium carbonate. To this mixture was added a solutionof benzoyl chloride. After two hours, the organic layer was separated,washed, and purified by flash chromatography.

[0131]¹H NMR (300 MHz, DMSO-d₆) δ 12.26 (br s), 8.63 (d), 8.04 (m),7.81-7.22 (m), 6.83 (m), 6.32 (m), 5.18 (m), 4.45 (m), 3.93 (s), 3.70(m), 3.33 (br s), 3.14-2.97 (m), 2.84 (m), 2.05 (br m); MS APCI, m/z=574(M⁺).

1. A compound of the formula (I): R¹R²N—CH₂CH₂—CHAr¹—CH₂—NR³—CO—R⁴  (I)wherein: R¹ and R² are joined to form an optionally substitutedmorpholino ring; Ar¹ is phenyl mono- or di-substituted by halo; R³ ishydrogen or C₁₋₆alkyl; R⁴ is optionally substituted naphth-1-yl; orpharmaceutically acceptable salts thereof.
 2. A compound according toclaim 1 wherein R¹ and R² together with the nitrogen atom to which theyare attached form a morpholino ring.
 3. A compound according to claim 1,wherein R⁴ is naphthyl which is unsubstituted or is substituted by up tothree substituents selected from cyano; nitro; C₁₋₆alkylsulfonyl; halo;C₁₋₆alkoxy; methylenedioxy (—OCH₂O—); C₁₋₆alkyl; C₂₋₆alkenyl;C₂₋₆alkynyl; C₁₋₆alkyl-carbamoyl; di-C₁₋₆alkylcarbamoyl; C₁₋₆alkanoyl;C₁₋₆alkanoylamino; aminosulfonyl; and cyanoC₁₋₆alkyl.
 4. A compoundaccording to claim 3, wherein R⁴ is naphthyl which is unsubstituted oris substituted by up to three substituents selected from cyano, methoxy,ethoxy, isopropoxy, fluoro, bromo, chloro, iodo, nitro, cyanomethyl,carboxy, carbamoyl, ethynyl, methyl, ethyl, dimethylcarbamoyl,methylsulfonyl, aminosulfonyl, prop-2-enyl, acetyl and acetylamino.
 5. Acompound according to claim 3, wherein R⁴ is naphthyl which isunsubstituted or is substituted by up to two substituents selected fromcyano, methoxy, ethyl, fluoro and nitro.
 6. A compound according toclaim 5, wherein R⁴ is 3-cyanonaphth-1-yl, 3-cyano-2-methoxynaphth-1-yl,2,3-dimethoxynaphth-1-yl or 3-cyano-2-ethylnaphth-1-yl.
 7. Apharmaceutical composition which comprises a compound according to claim1, and a pharmaceutically acceptable carrier or diluent.
 8. A method oftreating a disease condition selected from rheumatoid arthritis,Alzheimer's disease, schizophrenia, oedema, allergic rhinitis,inflammation, pain, gastrointestinal-hypermotility, gastric asthma,gastroesphageal reflux, anxiety, emesis, Huntington's Disease,psychoses, depression, hypertension, migraine and urticaria, whichcomprises administering to a warm-blooded animal atherapeutically-effective amount of a compound according to claim 1.